Differential modulation of short-term plasticity at hippocampal mossy fiber and Schaffer collateral synapses by mitochondrial Ca2.

Sang Hun Lee,Michael Frotscher,David Lutz,Jie Shen,Dagmar Drexler,Stephen D Ginsberg

doi:10.1371/journal.pone.0240610

Abstract

Presynaptic mitochondrial Ca2+ plays a critical role in the regulation of synaptic transmission and plasticity. The presynaptic bouton of the hippocampal mossy fiber (MF) is much larger in size than that of the Schaffer collateral (SC) synapse. Here we compare the structural and physiological characteristics of MF and SC presynaptic boutons to reveal functional and mechanistic differences between these two synapses. Our quantitative ultrastructural analysis using electron microscopy show many more mitochondria in MF presynaptic bouton cross-section profiles compared to SC boutons. Consistent with these results, post-tetanic potentiation (PTP), a form of presynaptic short-term plasticity dependent on mitochondrial Ca2+, is reduced by inhibition of mitochondrial Ca2+ release at MF synapses but not at SC synapses. However, blockade of mitochondrial Ca2+ release results in reduction of PTP at SC synapses by disynaptic MF stimulation. Furthermore, inhibition of mitochondrial Ca2+ release selectively decreases frequency facilitation evoked by short trains of presynaptic stimulation at MF synapses, while having no effect at SC synapses. Moreover, depletion of ER Ca2+ stores leads to reduction of PTP at MF synapses, but PTP is unaffected by ER Ca2+ depletion at SC synapses. These findings show that MF and SC synapses differ in presynaptic mitochondrial content as well as mitochondrial Ca2+ dependent synaptic plasticity, highlighting differential regulatory mechanisms of presynaptic plasticity at MF and SC synapses.

Highlights

The hippocampus is divided into three main fields, the dentate gyrus (DG) and areas CA3 and CA1, and each field displays distinctive anatomical, molecular, and biophysical properties [1, 2]
These findings show that mossy fiber (MF) and Schaffer collateral (SC) synapses differ in presynaptic mitochondrial content as well as mitochondrial Ca2+ dependent synaptic plasticity, highlighting differential regulatory mechanisms of presynaptic plasticity at MF and SC synapses
Using another specific inhibitor of mitochondrial Na+/Ca2+ exchanger (NCX), tetraphenylphosphonium (TPP+; 2 μM, for 15 min) [32, 33], we found that TPP+ treatment leads to a significant reduction of post-tetanic potentiation (PTP) in the MF pathway (Control: 194.0 ± 5.2%; +TPP: 147.2 ± 2.7%; p < 0.0001, paired t-test; Fig 2E–2G)

Summary

Introduction

The hippocampus is divided into three main fields, the dentate gyrus (DG) and areas CA3 and CA1, and each field displays distinctive anatomical, molecular, and biophysical properties [1, 2]. MF synapses between granule cells of the dentate gyrus and pyramidal neurons of the CA3 region are known to exhibit unique ultrastructural characteristics compared with other hippocampal synapses, and their presynaptic terminals are called ‘giants’ boutons [9]. Proper axonal transport and synaptic distribution of mitochondria and/or endoplasmic reticuli (ER) has been shown to play a crucial role in the maintenance of synaptic homeostasis during neuronal activity. Presynaptic mitochondria and ER contribute to the regulation of synaptic transmission and plasticity by sequestering Ca2+, thereby accelerating functional recovery during periods of moderate-to-high presynaptic activity [16]. Disruptions of mitochondrial or ER Ca2+ homeostasis at presynaptic axon terminals results in aberrant synaptic transmission [17,18,19,20]. Many neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, involve defects in mitochondrial and/or ER function and transport [21,22,23,24,25]

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Discussion

Conclusion